Tobacco use is a chronic relapsing disorder. Recurrent resumption of tobacco use after abstinence is one of the principal characteristics of nicotine addiction. Only approximately 3% of smokers successfully remain abstinent each year. The very high vulnerability to relapse following abstinence presents a formidable challenge for the treatment of nicotine addiction. One explanation for the persistence of addictive behavior and high risk of relapse after abstinence is the conditioning hypothesis, which is based on the observations that relapse is often associated with exposure to drug-related environmental stimuli. Over time, and after thousands of such pairings, the smoking-related stimuli (e.g., finishing a meal, the consumption of alcoholic beverages, being with friends who smoke, drinking coffee, reading the morning newspaper) become cues that elicit subjective states that can trigger craving, drug-seeking behavior and the resumption of nicotine use. The pervasive nature of these nicotine-associated cues in daily life suggests that cues might play a bigger role in nicotine addiction compared to other drugs of abuse. Although human studies have shown that environmental stimuli associated with nicotine use produce physiological and subjective changes in abstinent smokers, the significance of nicotine-related cues in triggering relapse has received little experimental attention. The proposed experiments are designed using an animal model of relapse to investigate the environmental and neuropharmacological bases of nicotine-seeking behavior associated with exposure to drug cues. The animal model will employ a response-reinstatement procedure where animals are initially trained to self-administer nicotine by pressing a lever in operant conditioning chambers and then the drug-reinforced behavior is extinguished by withholding the drug delivery. After extinction of the nicotine-reinforced behavior, the ability of nicotine-related stimuli (i.e., cues), nicotine itself (i.e., priming), and both to reinstate nicotine-seeking is determined. There has been an increasing use of these reinstatement procedures in recent years, and they have provided very important information on the neurobiological bases of drug (mainly cocaine and alcohol) use and relapse. The proposed experiments will characterize the motivational significance of nicotine-associated cues, nicotine priming, and their combination in an operant response-reinstatement model of relapse and determine whether the response-reinstating effects of nicotine cues, nicotine priming and their combination are sensitive to pharmacological antagonism of dopaminergic and nicotinic neurotransmission. The results of the proposed studies will provide important basic information on the role of nicotine-associated cues in the re-initiation of nicotine-seeking behavior. Results will not only lay the groundwork for future preclinical studies, but also will be useful in designing future trials to prevent relapse in humans.